ArticleMolecular therapy : the journal of the American Society of Gene Therapy2020
AAV1.SERCA2a Gene Therapy Reverses Pulmonary Fibrosis by Blocking the STAT3/FOXM1 Pathway and Promoting the SNON/SKI Axis.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 42 citations in OpenAlex.
- STAT3 Signaling in Spinal Cord Injury: Neurochemical Mechanisms Linking Neuroinflammation, Mitochondrial Stress, and Glial Remodeling.Neurochemical research · 2026Review
- BCL-XL drives fibrotic and leukemic progression in myeloproliferative neoplasms.Frontiers in immunology · 2026Article
- FOXM1 as a candidate dosage rheostat and state selector in breast cancer: linking multilevel regulation to adaptive plasticity and therapy resistance.Frontiers in oncology · 2026Review
- Review
- Emerging Perspectives in Anti-aging Treatments Using Anti-Fibrotic Strategies.Aging and disease · 2025Review
- Pharmacological inhibition of Epac1 protects against pulmonary fibrosis by blocking FoxO3a neddylation.The European respiratory journal · 2025Article
- Role of macrophage ATP metabolism disorder in SiOPurinergic signalling · 2025Review
- Pulmonary fibrosis: from mechanisms to therapies.Journal of translational medicine · 2025Review
- An anti-FAP-scFv-functionalized exosome-carrying hydrogel deliversTheranostics · 2025Article
- Current Understanding of Pulmonary Fibrosis: Pathogenesis, Diagnosis, and Therapeutic Approaches.Canadian respiratory journal · 2025Review
- The Role of Ubiquitin-Proteasome System (UPS) in Asthma Pathology.Journal of asthma and allergy · 2025Review
- Baicalin protects retinal ganglion cells by regulating microglial polarization and ferroptosis via the JAK2/STAT3 pathway.Frontiers in pharmacology · 2025Article
- Type I collagen-targeted liposome delivery of Serca2a modulates myocardium calcium homeostasis and reduces cardiac fibrosis induced by myocardial infarction.Materials today. Bio · 2024Article
- RNA-sequencing reveals differential fibroblast responses to bleomycin and pneumonectomy.Physiological reports · 2024Article
- Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis.Open medicine (Warsaw, Poland) · 2024Article
- The Interaction of OTUB1 and TRAF3 Mediates NLRP3 Inflammasome Activity to Regulate TGF-β1-induced BEAS-2B Cell Injury.Applied biochemistry and biotechnology · 2023Article
- FOXM1: Functional Roles of FOXM1 in Non-Malignant Diseases.Biomolecules · 2023Review
- OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2.Signal transduction and targeted therapy · 2023Article
- Wilms Tumor 1-Driven Fibroblast Activation and Subpleural Thickening in Idiopathic Pulmonary Fibrosis.International journal of molecular sciences · 2023Review
- RNF2 mediates pulmonary fibroblasts activation and proliferation by regulating mTOR and p16-CDK4-Rb1 signaling pathway.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Article
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
Inhibition of pulmonary fibrosis (PF) by restoring sarco/endoplasmic reticulum calcium ATPase 2a isoform (SERCA2a) expression using targeted gene therapy may be a potentially powerful new treatment approach for PF. Here, we found that SERCA2a expression was significantly decreased in lung samples from patients with PF and in the bleomycin (BLM) mouse model of PF. In the BLM-induced PF model, intratracheal aerosolized adeno-associated virus serotype 1 (AAV1) encoding for human SERCA2a (AAV1.hSERCA2a) reduces lung fibrosis and associated vascular remodeling. SERCA2a gene therapy also decreases right ventricular pressure and hypertrophy in both prevention and curative protocols. In vitro, we observed that SERCA2a overexpression inhibits fibroblast proliferation, migration, and fibroblast-to-myofibroblast transition induced by transforming growth factor β (TGF-β1). Thus, pro-fibrotic gene expression is prevented by blocking nuclear factor κB (NF-κB)/interleukin-6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3) activation. This effect is signaled toward an inhibitory mechanism of small mother against decapentaplegic (SMAD)/TGF-β signaling through the repression of OTU deubiquitinase, ubiquitin aldehyde binding 1 (OTUB1) and Forkhead box M1 (FOXM1). Interestingly, this cross-inhibition leads to an increase of SKI and SnoN expression, an auto-inhibitory feedback loop of TGF-β signaling. Collectively, our results demonstrate that SERCA2a gene transfer attenuates bleomycin (BLM)-induced PF by blocking the STAT3/FOXM1 pathway and promoting the SNON/SKI Axis. Thus, SERCA2a gene therapy may be a potential therapeutic target for PF.
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